PLCE1 explained

Phospholipase C epsilon 1 (PLCE1) is an enzyme that in humans is encoded by the PLCE1 gene.^{[1] [2]} This gene encodes a phospholipase enzyme (PLCE1) that catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to generate two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Mutations in this gene cause early-onset nephrotic syndrome and have been associated with respiratory chain deficiency with diffuse mesangial sclerosis.^{[3] [4]}

Structure

PLCE1 is located on the q arm of chromosome 10 in position 23.33 and has 39 exons. PLCE1, the protein encoded by this gene, is located on the Golgi apparatus, the cell membrane, and in the cytosol. It contains 3 turns, 15 beta strands, and 6 alpha helixes. PLCE1 contains a 260 amino acid Ras-GEF domain at p. 531-790, a 149 amino acid PI-PLC X-box domain at p. 1392-1540, a 117 amino acid PI-PLC Y-box domain at p. 1730 – 1846, a 101 amino acid C2 domain at p. 1856 – 1956, a 103 amino acid Ras-associating 1 domain at p. 2012 – 2114, and a 104 amino acid Ras-associating 2 domain at p. 2135 – 2238. There is a region of 79 amino acids from p. 1686 – 1764 that is required for PLCE1 to be activated by RHOA, RHOB, GNA12, GNA13 and G-beta gamma. PLCE1 also has a Ca2+ cofactor.^{[5] [6]} Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Function

PLCE1 belongs to the phospholipase family that catalyzes the hydrolysis of polyphosphoinositides such as phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to generate the second messengers Ins(1,4,5)P3 and diacylglycerol. These products initiate a cascade of intracellular responses that result in cell growth and differentiation and gene expression.[supplied by OMIM]

Catalytic activity

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O = 1D-myo-inositol 1,4,5-trisphosphate + diacylglycerol.

Clinical significance

Mutations in this gene cause early-onset nephrotic syndrome. This disease is characterized by proteinuria, edema, and diffuse mesangial sclerosis or focal and segmental glomerulosclerosis. Signs and symptoms include kidney biopsies demonstrating non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation as well as genetic tests revealing a pathogenic S1484L mutation. Diffuse mesangial proliferation is characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen.^[7] This disease has also been associated with mitochondrial cytopathy stemming from respiratory chain deficiency primarily affecting complex IV.

Additionally, Phospholipase C epsilon modulates beta-adrenergic receptor-dependent cardiac contraction and it has been found that this protein is over expressed during heart failure. Research has suggested that PLCE1 may thus inhibit cardiac hypertrophy.^[8]

PLCE1 gene polymorphism increases susceptibility to oesophageal, gastric, colon, and squamous cell carcinoma of the head and neck area. It is shown that PLCE1 is highly expressed in osteosarcoma and regulates its proliferation and invasion. PLCE1 also affects the survival of patients with osteosarcoma. Therefore, it is suggested as a potential diagnostic biomarker and molecular therapeutic target for osteosarcoma.^[9]

Interactions

PLCE1 has been shown to have 12 binary protein-protein interactions including 8 co-complex interactions. PLCE1 appears to interact with RyR2, HRAS, NRAS, and LIMS1.^[10]

Further reading

• Jefferson JA, Shankland SJ . Familial nephrotic syndrome: PLCE1 enters the fray . Nephrology, Dialysis, Transplantation . 22 . 7 . 1849–52 . July 2007 . 17449496 . 10.1093/ndt/gfm098 . free .
• Cefai D, Debre P, Kaczorek M, Idziorek T, Autran B, Bismuth G . Human immunodeficiency virus-1 glycoproteins gp120 and gp160 specifically inhibit the CD3/T cell-antigen receptor phosphoinositide transduction pathway . The Journal of Clinical Investigation . 86 . 6 . 2117–24 . December 1990 . 1979339 . 329852 . 10.1172/JCI114950 .
• Zauli G, Previati M, Caramelli E, Bassini A, Falcieri E, Gibellini D, Bertolaso L, Bosco D, Robuffo I, Capitani S . Exogenous human immunodeficiency virus type-1 Tat protein selectively stimulates a phosphatidylinositol-specific phospholipase C nuclear pathway in the Jurkat T cell line . European Journal of Immunology . 25 . 9 . 2695–700 . September 1995 . 7589147 . 10.1002/eji.1830250944 . 20562627 .
• Chen P, Mayne M, Power C, Nath A . The Tat protein of HIV-1 induces tumor necrosis factor-alpha production. Implications for HIV-1-associated neurological diseases . The Journal of Biological Chemistry . 272 . 36 . 22385–8 . September 1997 . 9278385 . 10.1074/jbc.272.36.22385 . free .
• Mayne M, Bratanich AC, Chen P, Rana F, Nath A, Power C . HIV-1 tat molecular diversity and induction of TNF-alpha: implications for HIV-induced neurological disease . Neuroimmunomodulation . 5 . 3–4 . 184–92 . 1998 . 9730685 . 10.1159/000026336 . 19529677 .
• Haughey NJ, Holden CP, Nath A, Geiger JD . Involvement of inositol 1,4,5-trisphosphate-regulated stores of intracellular calcium in calcium dysregulation and neuron cell death caused by HIV-1 protein tat . Journal of Neurochemistry . 73 . 4 . 1363–74 . October 1999 . 10501179 . 10.1046/j.1471-4159.1999.0731363.x . 25410140 . free .
• Nagase T, Kikuno R, Ishikawa K, Hirosawa M, Ohara O . Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro . DNA Research . 7 . 2 . 143–50 . April 2000 . 10819331 . 10.1093/dnares/7.2.143 . free .
• Mayne M, Holden CP, Nath A, Geiger JD . Release of calcium from inositol 1,4,5-trisphosphate receptor-regulated stores by HIV-1 Tat regulates TNF-alpha production in human macrophages . Journal of Immunology . 164 . 12 . 6538–42 . June 2000 . 10843712 . 10.4049/jimmunol.164.12.6538 . free .
• Jin TG, Satoh T, Liao Y, Song C, Gao X, Kariya K, Hu CD, Kataoka T . Role of the CDC25 homology domain of phospholipase Cepsilon in amplification of Rap1-dependent signaling . The Journal of Biological Chemistry . 276 . 32 . 30301–7 . August 2001 . 11395506 . 10.1074/jbc.M103530200 . free .
• Schmidt M, Evellin S, Weernink PA, von Dorp F, Rehmann H, Lomasney JW, Jakobs KH . A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase . Nature Cell Biology . 3 . 11 . 1020–4 . November 2001 . 11715024 . 10.1038/ncb1101-1020 . 6423723 .
• Evellin S, Nolte J, Tysack K, vom Dorp F, Thiel M, Weernink PA, Jakobs KH, Webb EJ, Lomasney JW, Schmidt M . Stimulation of phospholipase C-epsilon by the M3 muscarinic acetylcholine receptor mediated by cyclic AMP and the GTPase Rap2B . The Journal of Biological Chemistry . 277 . 19 . 16805–13 . May 2002 . 11877431 . 10.1074/jbc.M112024200 . free .
• Song C, Satoh T, Edamatsu H, Wu D, Tadano M, Gao X, Kataoka T . Differential roles of Ras and Rap1 in growth factor-dependent activation of phospholipase C epsilon . Oncogene . 21 . 53 . 8105–13 . November 2002 . 12444546 . 10.1038/sj.onc.1206003 . free .
• Bennasser Y, Badou A, Tkaczuk J, Bahraoui E . Signaling pathways triggered by HIV-1 Tat in human monocytes to induce TNF-alpha . Virology . 303 . 1 . 174–80 . November 2002 . 12482669 . 10.1006/viro.2002.1676 . free .
• Czyzyk J, Brogdon JL, Badou A, Henegariu O, Preston Hurlburt P, Flavell R, Bottomly K . Activation of CD4 T cells by Raf-independent effectors of Ras . Proceedings of the National Academy of Sciences of the United States of America . 100 . 10 . 6003–8 . May 2003 . 12721365 . 156316 . 10.1073/pnas.1031494100 . 2003PNAS..100.6003C . free .
• Lennartsson J, Wernstedt C, Engström U, Hellman U, Rönnstrand L . Identification of Tyr900 in the kinase domain of c-Kit as a Src-dependent phosphorylation site mediating interaction with c-Crk . Experimental Cell Research . 288 . 1 . 110–8 . August 2003 . 12878163 . 10.1016/S0014-4827(03)00206-4 .
• vom Dorp F, Sari AY, Sanders H, Keiper M, Oude Weernink PA, Jakobs KH, Schmidt M . Inhibition of phospholipase C-epsilon by Gi-coupled receptors . Cellular Signalling . 16 . 8 . 921–8 . August 2004 . 15157671 . 10.1016/j.cellsig.2004.01.009 .

Notes and References

1. Lopez I, Mak EC, Ding J, Hamm HE, Lomasney JW . A novel bifunctional phospholipase c that is regulated by Galpha 12 and stimulates the Ras/mitogen-activated protein kinase pathway . The Journal of Biological Chemistry . 276 . 4 . 2758–65 . January 2001 . 11022047 . 10.1074/jbc.M008119200 . free .
2. Song C, Hu CD, Masago M, Kariyai K, Yamawaki-Kataoka Y, Shibatohge M, Wu D, Satoh T, Kataoka T . Regulation of a novel human phospholipase C, PLCepsilon, through membrane targeting by Ras . The Journal of Biological Chemistry . 276 . 4 . 2752–7 . January 2001 . 11022048 . 10.1074/jbc.M008324200 . free .
3. Web site: Entrez Gene: PLCE1 phospholipase C, epsilon 1.
4. Baskin E, Selda Bayrakci U, Alehan F, Ozdemir H, Oner A, Horvath R, Vega-Warner V, Hildebrandt F, Ozaltin F . Respiratory-chain deficiency presenting as diffuse mesangial sclerosis with NPHS3 mutation . Pediatric Nephrology . 26 . 7 . 1157–61 . July 2011 . 21365190 . 3329966 . 10.1007/s00467-011-1814-0 .
5. Web site: PLCE1 - 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 - Homo sapiens (Human) - PLCE1 gene & protein. www.uniprot.org. en. 2018-08-30.
6. UniProt: the universal protein knowledgebase . Nucleic Acids Research . 45 . D1 . D158–D169 . January 2017 . 27899622 . 5210571 . 10.1093/nar/gkw1099 .
7. Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nürnberg G, Garg P, Verma R, Chaib H, Hoskins BE, Ashraf S, Becker C, Hennies HC, Goyal M, Wharram BL, Schachter AD, Mudumana S, Drummond I, Kerjaschki D, Waldherr R, Dietrich A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M, Griebel M, Tsygin AN, Soylu A, Müller D, Sorli CS, Bunney TD, Katan M, Liu J, Attanasio M, O'toole JF, Hasselbacher K, Mucha B, Otto EA, Airik R, Kispert A, Kelley GG, Smrcka AV, Gudermann T, Holzman LB, Nürnberg P, Hildebrandt F . 6 . Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible . Nature Genetics . 38 . 12 . 1397–405 . December 2006 . 17086182 . 10.1038/ng1918 . 4037950 .
8. Wang H, Oestreich EA, Maekawa N, Bullard TA, Vikstrom KL, Dirksen RT, Kelley GG, Blaxall BC, Smrcka AV . Phospholipase C epsilon modulates beta-adrenergic receptor-dependent cardiac contraction and inhibits cardiac hypertrophy . Circulation Research . 97 . 12 . 1305–13 . December 2005 . 16293787 . 10.1161/01.RES.0000196578.15385.bb . free .
9. Huang . Linhai . Liao . Chundi . Wu . Hanhua . Huang . Piwei . 2022-06-26 . PLCE1 is a poor prognostic marker and may promote immune escape from osteosarcoma by the CD70-CD27 signaling pathway . Bosnian Journal of Basic Medical Sciences . 22 . 6 . 992–1004 . en . 10.17305/bjbms.2022.7416 . 35765945 . 9589306 . 250080062 . 1840-4812. free .
10. Web site: IntAct Portal. IntAct. www.ebi.ac.uk. en. 2018-08-30.